Disclosures: Dr. Trauner disclosed relationships with Gilead, Albireo, Takeda, Falk Pharma, Genfit, Intercept, MSD, Novartis, Roche, and Phenex, and is listed as a coinventor on patents filed for the medical use of 24-nor-ursodeoxycholic acid.

AT THE LIVER MEETING 2017

WASHINGTON – Limited treatment options for nonalcoholic steatohepatitis (NASH) in nonalcoholic fatty liver disease mean that NASH is the fastest-growing reason for liver transplants in the United States, but preclinical and, now, phase 2 clinical results have shown that treatment with 24-nor-ursodeoxycholic acid, otherwise known as norUDCA, can improve steatosis and liver stiffness in selected patients, a principal investigator in a European study of the treatment reported at the 2017 annual meeting of the American Association for the Study of Liver Diseases.

“The norUDCA dose of 1,500 mg resulted in significant reduction of ALT [alanine aminotransferase] within 12 weeks,” said Michael Trauner, MD, head of the division of gastroenterology and hepatology at the Medical University of Vienna, a coinventor of the drug. “The results are supported by improvement in liver stiffness and steatosis in the subsets analyzed.”

Dr. Michael Trauner

The trial involved 198 patients with NAFLD randomized to a 12-week treatment with either 500 mg or 1,500 mg norUDCA or placebo and 4 weeks of follow-up. Average ALT levels at enrollment ranged from 77.4 to 80.3 U/L, and most patients had mild or no fibrosis based on noninvasive markers (NAFLD fibrosis score) – 64.5% in the placebo group and around 80% in the two treatment groups. Rates of diabetes ranged from 6% to 15.6%.

The 1,500-mg group had an average reduction in ALT of 17.4% whereas those in the 500-mg group only had a 4.2% reduction and placebo actually had an increase of 10.4%. “The reduction of the 500-mg dose was not significant,” Dr. Trauner said. “And this was emphasized in the proportion of patients reaching ALT less than 0.8 x ULN (upper limits of normal) at the end of treatment, with about 17% of patients reaching this endpoint in the higher dose group.” Among patients in the 500-mg group, 15% achieved that level, as did 5% in the placebo group.

The therapy also had an effect on lipid levels, Dr. Trauner noted. “Surprisingly, we saw a slight increase in LDL levels, with the highest in the 1,500-mg dose,” he said. “There were no significant changes in triglycerides and HDL levels, although there were some trends for reduced triglycerides and increased HDL.” Triglycerides decreased 14.6 mg/dL on average and HDL increased 2.8 mg/dL. The slight rise in LDL, 14.6 mg/dL on average, occurred in the first 2 weeks of treatment and continued through the treatment period, but then receded after discontinuation of therapy, said Dr. Trauner. “Please note that HDL cholesterol also increased in time, and the HDL-LDL ratio remained unchanged in these patients,” he added.

During the discussion, Dr. Trauner offered a possible explanation for the change in lipid levels. “One possibility could be that a slight repression of endogenous bile acid biosynthesis and subsequent upregulation of the LDL receptor,” he said, “but the changes are really very mild and subtle.”

He also noted that liver stiffness improved in a higher proportion of patients in the treatment groups than in the placebo group – 25% and 21% of patients in the 1,500- and 500-mg groups vs. 9% under placebo. Hepatic fat fraction values also improved from 21.3% to 16.3% (relative reduction of 23.5%) from baseline to end of treatment in the 1,500-mg group in a subset of patients undergoing more extensive MRI and spectroscopy studies – a degree of reduction that other studies have shown to be predictive of histologic improvement, Dr. Trauner said. Patients in this exploratory study did not have liver biopsies.

Overall, the drug was well tolerated, Dr. Trauner said. “There were slightly higher potentially adverse drug reactions in the 1,500-mg group, mainly due to higher rate of headache, nausea, and rash,” he said. Based on these results, a phase 2b study with histologic endpoints is underway, he added.